This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To understand the pharmacokinetics of the highly active anti-retroviral therapy (HAART) regimen, combinations of protease inhibitors (HPIs) in humans with HIV-AIDS, preclinical studies had previously analyzed both P-gp (an ABCtransporter) and Cyp3A4 (a CYP-450 isozyme) expression in small animal models, such as mice, rats and rabbits, where bioavailability and peak plasma levels were determined as a measure of anti-HIV efficacy of HPIs. However, recent studies demonstrated significant species specific variations in the expression of both ABC-transporters and CYP-450 isozymes which may profoundly alter the correct determination of therapeutic dosing of HPIs, especially in the GI-submucosa of HIV-positive patients. We plan to develop an ex vivo model of SIV persistence in intestinal reservoirs despite antiretroviral therapy, and identify novel strategies towards inhibition of the host factors which cause this inefficacy. We hypothesize that both P-gp and Cyp3A4 suppress HPI transport across intestinal barriers and strategies towards their inhibition will abrogate the persistence of submucosal viral reservoirs in SIVinfected monkey models. The project start date is pending on the submission to and approval of the IACUC application.